Neurological disorders and diseases of the brain are increasingly prevalent health concerns due to an aging population, increased awareness of long term effects of traumatic brain injury, and incidence of brain cancer. Treating the brain presents a unique challenge for due to the delicate nature of the tissue and privileged environment due to the blood-brain barrier. Drug delivery systems have been used to ferry drugs to the brain and central nervous system (CNS), however cerebrospinal fluid (CSF) turnover can rapidly clear drugs from the CNS and reduce treatment efficacy. This proposal will explore strategies to locally deliver drugs to the brain and reduce drug efflux by modulating CSF production. This proposal will test the hypothesis that CSF dynamics affect drug exposure in the CNS. During the mentored phase, I will learn device fabrication techniques and develop drug delivery micro devices capable of locally delivering multiple compounds into the brain parenchyma. Development of these devices is necessary, as many drugs do not efficiently cross into the brain when administered systemically. I will use these devices and in vivo imaging techniques to quantify how CSF-modulating drugs such as acetazolamide affect drug distribution and exposure. The data and skills acquired during the mentored phase will lead to the evaluation of CSF-modulating drug delivery systems in rodent models of brain cancer during the independent phase of this grant. During the independent phase, I will combine my background in chemistry and animal models of disease with newly learned fabrication expertise and explore the relationship between reducing CSF efflux of drugs and treatment efficacy in rodent models of brain disease. I will test the effectiveness of these drug delivery systems using rodent models of brain cancer and design new, molecular delivery vehicles. This line of research will lead to more effective ways to treat brain cancers, neurodegenerative diseases, and other diseases of the brain.